This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In response to an acute myocardial infarction, the mammalian heart responds with formation of collagen-laden scar tissue. In contrast, the zebrafish heart will undergo cardiomyocyte (CM) proliferation to repair the damaged or missing portion of the myocardial wall, thereby enabling complete restoration of cardiac function. Why certain organisms are better equipped to regenerate lost and damaged tissue has been the subject of intense studies for over three centuries. Yet to date, we know very little about the genetics that stimulate organ regeneration. It is clear however, that the transformation from a differentiated tissue into highly proliferative and regenerative cells requires dramatic changes in developmental programs. In this proposal I will examine the contributions of microRNAs (miRNAs) as modulators of changes in genetic programs during heart regeneration by focusing on the role of the key processing enzyme, Dicer and two specific miRNAs, miR-21 and miR133. For my studies, I will use the powerful, vertebrate zebrafish as a genetic model system due to its robust capacity for heart regeneration. My goal for this research is to ascertain how tissue-specific miRNAs are regulating cardiac regeneration through the use of inducible transgenic strains that modify miRNA activity. My studies will enhance potential therapies to increase survival and regeneration of adult cardiac muscle following ischemic injury.